Sucralfate preparations

ABSTRACT

Sucralfate containing preparations which contain both an organic acid having at least two carboxyl groups or at least one carboxyl group in the molecule and sucralfate are described. The sucralfate containing preparations have enhanced sucralfate adhesion to the mucosal ulcer site even under a nonacidic condition and can be extensively applied not only to ulcers in the upper digestive tract such as esophagitis and duodenal ulcer but also to ulcers in the lower digestive tract such as proctitis and ulcerative colitis, as well as to dermal ulcers such as bedsores, stomatitis and the like.

This is a 371 of PCT/JP96/00217 filed Feb. 2, 1996.

TECHNICAL FIELD

This invention relates to sucralfate containing preparations that can beapplied to mucosal damage and the like in a nonacidic condition and,more particularly, it relates to sucralfate preparations containing bothan organic carboxylic acid having at least two carboxyl groups or atleast one hydroxyl group in the molecule and sucralfate.

BACKGROUND ART

Sucralfate is a medicine that is described in the Japanese Pharmacopoeiaand commonly used as a therapeutic for gastric and duodenal ulcers. Themechanism of its action is known to be attributable to antipepsin andantacid effects and the like. Two principal effects of sucralfate arebelieved to be forming a highly adhesive gel under an acidic conditionto cover an ulcerated surface and in binding with plasma proteins underan acidic condition to cover the ulcerated surface (i.e., a mucosaprotecting action). However, for selective binding to the mucosal ulcersite, the formation of a gel under the acidic condition caused bygastric acid is essential and in areas where acids are absent such asthe small intestine, colon and the skin, no chemical binding andadhesion to the ulcer site occurs, except by physical adsorption.

There have been very few cases of the application of sucralfate whichhas been provided with enhanced adhesion to mucous membranes as in thesmall intestine and colon and the only exception is found in JapanesePatent Public Disclosure No. 190127/1987, which describes theapplication of added, collagen to the wound site. In known cases ofsucralfate application to ulcerative colitis, sucralfate suspensionsprepared with methylcellulose, propylcellulose and the like being addedas thickeners are administered by the enteral route (see Scand. J.Gastroenterol., vol. 24, pp. 1014, 1989, Endoscopy, vol. 18, pp. 115,1986, etc.) but these preparations have encountered several problems,one of which is that adhesion to the ulcer site is not expected.

As for the addition of organic acids to sucralfate, Japanese PatentPublication No. 35130/1993 describes the case of adding a phosphate orcitrate to a sucralfate suspension. In this case, the organic acid saltsare utilized to enhance the dispersibility of the suspension. However,enhanced adhesion to the ulcer site is not expected. Japanese PatentDomestic Announcement No. 500052/1993 discloses the technique ofpreparing effervescent tablets by adding an organic acid and a carbonateto sucralfate. However, the purpose of this proposal is the applicationof effervescent sucralfate tablets to the stomach and the use ofcarbonates is not intended to enhance the adhesion to the ulcer site.

DESCRIPTION OF INVENTION

In view of the above-described problems of the prior art, the presentinventors conducted intensive studies on sucralfate preparations whichwould provide for effective adhesion of sucralfate to the mucosal ulcersite under a nonacidic condition; as a result, they found thatsucralfate preparations containing both an organic carboxylic acidhaving at least two carboxyl groups or at least one hydroxyl group inthe molecule and sucralfate permitted enhanced adhesion of sucralfate tothe mucosal ulcer site under a nonacidic condition and this finding hasled to the accomplishement of the present invention.

BRIEF DESCRIPTION OF THE INVENTION

FIG. 1 is a graph showing the BSA binding ratios of various addedorganic carboxylic acids and their acid to sucralfate equivalent ratios.

The organic carboxylic acid to be used in the invention is one having atleast two carboxyl groups or at least one hydroxyl group in themolecule. Among such organic carboxylic acids, those which have at least5% solubility, preferably at least 10% solubility, in water can be usedwith advantage.

As for the acid dissocation constant (pKl) of the organic carboxylicacid to be used in the invention, values of no more than 4 arepreferred. Organic carboxylic acids having pKl values of more than 4will not react readily with sucralfate and they are not expected toachieve enhanced adhesion which is the principal object of theinvention.

Organic carboxylic acids that satisfy these conditions include citricacid, malic acid, maleic acid, tartaric acid, lactic acid, gluconic acidand glucuronic acid, with citric acid and malic acid being preferablyused. Malic acid is more preferred.

The compositional ratio of the organic carboxylic acid to sucralfate inthe sucralfate preparation of the invention ranges typically from 1:1 to1:20, preferably from 1:3 to 1:10, on a weight basis with the lowerlimit being between 1:1 and 1:3 and the upper limit between 1:15 and1:20. If the compositional ratio of the organic carboxylic acid is lessthan the above-mentioned range, sucralfate will not be adherent; in theopposite case, the organic carboxylic acid may dissolve the sucralfateor the irritating effect of the excess organic carboxylic acid may comeinto play and either situation is not suitable for practicalpreparations.

The above-mentioned organic carboxylic acids may be as a powder or asolution in the preparation. Sucralfate and the organic carboxylic acidmay be present as separate entities in the preparation or,alternatively, they may be preliminarily reacted with each other beforeuse.

The sucralfate to be used in the invention may be of any type such asone commercially available under the trade name of "Ulcerlmin"(registered trademark of Chugai Pharmaceutical Co., Ltd.) or oneobtained by various synthesis procedures. When it is to be synthesize,sucralfate may be produced by the methods described in, for example,Japanese Patent Publication Nos. 11673/1969, 16037/1969 and 76927/1993,International Publication WO 9204030, etc. The wet powder which isobtained in each of the synthesis procedures or the sucralfate obtainedby drying said powder may also be employed.

The sucralfate preparation of the invention may be used in variousdosage forms including tablets, granules, subtilized granules, capsules,powders, troches, suppositories, pills, chewable tablets, solutions,emulsions, suspensions, lotions, ointments, cataplasms and elixirs.Pharmaceutical formulation of these dosage forms may be performed withvarious ancillaries added, such as pharmacologically acceptable suitableliquid or solid vehicles, excipients, dispersants, fillers, bulkingagents, solvents, emulsifiers, additives, lubricants, antiseptics,flavoring agents, wetting agents, flavor correctives, dyes and buffers.

Solid preparations such as tablets, granules, subtilized granules,capsules, powders, troches, pills and chewable tablets can be formulatedby the conventional procedures in the presence of various additivesincluding vehicles such as sodium bicarbonate, calcium carbonate,starches, sucrose, mannitol and carboxymethylcellulose. Thesepreparations are preferred for peroral administration and applicable toulcers in the upper digestive tract such as esophagitis and duodenalulcer.

If desired, enteric coatings of cellulose acetate phthalate,hydroxypropyl methylcellulose phtalate, polyvinyl alcohol phthalate,styrene-maleic anhydride copolymer and methacrylic acid-methylmethacrylate copolymer may be applied to formulate enteric preparationswhich will disintegrate in the small intestine, colon and the like.

To formulate solid preparations, sucralfate and an organic carboxylicacid may be individually granulated or otherwise processed in thepressence of suitable added ancillaries such as excipients and mixedinto a powder, which is administered either by itself or after beingshaped into capsules, tablets and the like. Alternatively, sucralfatedispersed in water may be reacted with an organic carboxylic acid andthe reaction product is dried to form a powder, which may similarly beshaped into capsules, tablets and the like.

Solutions may be formulated using solvents exemplified by purifiedwater, physiological saline, alcohols such as ethanol, propylene glycol,glycerin and polyethylene glycol, and triacetin. To formulate solutions,sucralfate and an organic carboxylic acid are placed in separatecontainers in the form of a suspension, solution or powder and, justbefore use, water is optionally added and the two ingredients are mixedtogether to form the solution. Alternatively, the two ingredients may bepreliminarily reacted with each other to form the solution.

To treat proctitis, ulcerative colitis and other diseases in the lowerdigestive tract, suspensions, solutions and the like may preferably beput into enemic containers to formulate enemas or suppositories may beformulated for administration by the enteral route. Alternatively,enteric granules, tablets, capsules, etc. may be formulated for peroraladministration. In other cases, sucralfate and an organic carboxylicacid may be processed into a gel in the presence of added water and asuitable base is added as required to formulate preparations forexternal application such as ointments and creams, which may be appliedto dermal ulcers such as bedsores, as well as ulcers of the oral mucosasuch as stomatitis. For the treatment of dermal ulcers such as bedsores,powders, suspensions and the like may also be formulated; for thetreatment of ulcers of the oral mucosa such as stomatitis, troches,suspensions, powders, granules, tablets and the like may also beformulated.

Hydrophilic polymers may be added to the scralfate preparation of theinvention to thereby impart viscosity such that the retention in theulcer site and the mucosal affinity are enhanced. Exemplary hydrophilicpolymers that may be employed for this purpose include alginic acid,sodium alginate, hydroxypropyl starch, a propylene glycol ester ofalginic acid, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, carboxymethyl cellulose, carboxymethycellulose sodium,carboxymethyl starch and carboxy vinyl polymers.

If the sucralfate preparation of the invention is to be used as asuspension, starches and/or starch derivatives are preferably used asdispersants and exemplary starches and/or starch derivatives includewheat starch, rice starch, corn starch, potato starch, glutinous cornstarch, glutinous rice starch, starch acetic acid esters, starchsuccinic acid esters, starch nitrate esters, starch phosphate esters,starch xanthogenic acid esters, starch allyl ether, starch methyl ether,starch carboxymethyl ether, starch hydroxyethyl ether and starchhydroxypropyl ether (hydroxypropyl starch), with hydroxypropyl starchbeing preferably used.

The scralfate preparation of the invention may be administered eitherorally or parenteraly such as by the enteral, buccal and topical routes.The dosage can be selected as appropriate for the dosage form to beadministered, the sex of the patient, physical makeup, constitution,age, etc.; typically, the drug may be applied 1-4 times a day, with thesingle dose being 5-200 mg/kg, preferably 10-100 mg/kg.

The invention will now be described in greater detail with reference tothe following examples, which are by no means intended to limit theinvention.

EXAMPLE 1

Sucralfate and an organic carboxylic acid (citric acid, malic acid,maleic acid, lactic acid, gluconic acid or glucuronic acid) were addedto 15 ml of a physiological saline solution of 0.5% bovine serum albumin(BSA) in amounts that were weighed to give a sucralfate to BSA ratio of0.05, 0.1 or 0.15. Following incubation at 37° C. for 30 min, themixture was increased in volume up to 100 ml and passed through a0.22-μm membrane filter to remove the BSA bound complexes, therebypreparing a sample solution. The percentage of BSA binding wasdetermined by measuring the quantity of BSA in the solution with aprotein assay reagent and the amount of sucralfate that would give 50%binding was determined. This was compared with the value of 50%sucralfate level as measured in a CLB buffer solution containing onlysucralfate and the resulting ratio was designated as a BSA bindingratio. This value represents the ease in binding to proteins andprovides an index of adhesion to the ulcer site. The BSA binding ratiosof systems having various organic carboxylic acids and control HCl addedare shown in FIG. 1.

With citric acid, malic acid, maleic acid, latic acid, gluconic acid andglucuronic acid, higher values were exhibited than with HCl andparticularly high values were exhibited with citric acid and malic acid.

EXAMPLE 2

Japanese albino rabbits were injected with 0.2 ml of 3% acetic acidsolution via a catheter through the anal portal to thereby create anacetic acid ulcer; one day later, sucralfate was mixed with citric acidand water to prepare a sample in a gel form, which was administered bythe enteral route via a catheter in an amount equivalent to 100 mg/kg ofsucralfate. At 3 hr after the administration, the rabbits were bled todeath and the large intestine was removed and both the ulcer and healthysites were sampled, each in a width of 1 cm; the adherent aluminum wasextracted and assayed by atomic absorption spectroscopy. The results areshown in Table 1.

                  TABLE 1                                                         ______________________________________                                                       Adhesion to                                                                             Adhesion to                                          Sucralfate:             ulcer site                                                                               healthy site                               citric acid                              (ppm)                                (weight ratio)    (Al μg/cm.sup.2 )                                                                  (Al μg/cm.sup.2)                                 ______________________________________                                        8:0            44.6      14.3                                                                                        (28.6)                                 8:1                                       19.0                                                                       (38.0)                                 6:1                                       16.6                                                                       (33.2)                                 4:1                                      22.3                                                                        (44.6)                                 3:1                                      16.9                                                                        (33.8)                                 ______________________________________                                    

Table 1 shows, the incorporation of citric acid was effective in causingthe sucralfate to adhere to the ulcer site selectively, with theadhesion being up to 5 times as large as in the case of sucralfate towhich citric acid was not added.

EXAMPLE 3

As in Example 2, an acetic acid ulcer was created in the largeintestines of Japanese albino rabbits. A sucralfate preparation wasformulated by adding malic acid to a 10% sucralfate suspensioncontaining 2.5% hydroxypropyl starch gel and it was administered by theenteral route with a catheter in an amount equivalent to 100 mg/kg ofsucralfate. At 3 h after the administration, the rabbits were bled todeath and the large intestine was removed and both the ulcer and analsites were sampled; the adherent aluminum was extracted and quantitated.The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Sucralfate:    Adhesion to                                                                             Adhesion to                                          malic acid               ulcer site                                                                             healthy site                                (weight ratio)       (μg/cm.sup.2)                                                                   (μg/cm.sup.2)                                    ______________________________________                                        8:0            2.26      1.95                                                 8:1                                     0.52                                  6:1                                      12.3                                 4:1                                      13.8                                 ______________________________________                                    

As Table 2 shows, the sucralfate in the sucralfate suspension whichwould readily disperse in the intestines adhered to the ulcer siteselectively; it was therefore found that the sucralfate adhesion hadbeen increased by the addition of malic acid.

EXAMPLE 4

The ingredients set forth in the following recipe were weighed, mixedand compressed to prepare tablets each weighing 293 mg.

    ______________________________________                                        Sucralfate, dried powder 200 mg                                               Citric acid                                            50 mg                  Carboxymethylcellulose calcium                                                                                  12.5 mg                                     Crystalline cellulose                        30 mg                            Magnesium stearate                             0.5 mg                         ______________________________________                                    

EXAMPLE 5

The ingredients set forth in the following recipe were weighed, mixedand filled into capsules. By subsequent coating with a coating solution(see below) to give a solids content of 10%, enteric capsules wereprepared.

(Capsule recipe)

    ______________________________________                                        Sucralfate, dried powder                                                                        80 parts                                                    Citrid acid                                     20 parts                      Macrogol 6000                                 10 parts                        ______________________________________                                    

(Coating recipe)

    ______________________________________                                        Hydroxypropyl methylcellulose phthalate                                                                 10 parts                                            Macrogol 6000                                        1 part                   Stearic acid                                          2 parts                 Methylene chloride                             50 parts                       Ethanol                                                   50                  ______________________________________                                                                  parts                                           

EXAMPLE 6

As in Example 2, an acetic acid ulcer was created in the largeintestines of Japanese albino rabbits. A sucralfate preparation (A) wasformulated by adding 1 ml of 19.2% malic acid to 10 ml of 10% sucralfatesuspension containing 2.5% hydroxypropyl starch gel; another sucralfatepreparation (B) was formulated by the same procedure except that noaqueous malic acid solution was added. Each of the sucralfatepreparations was administered by the enteral route with a catheter in anamount equivalent to 100 mg/kg of sucralfate. At 1 h, 3 h and 6 h afterthe administration, the rabbits were bled to death and the largeintestine was removed and the aluminum adhering to the ulcer site wasextracted and quantitated. The respective amounts of adhesion wereconverted to the sucralfate level. The results are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                        Group of preparation (A)                                                                        Group of preparation (B)                                    (μmol/cm.sup.2)                                                                                      (μmol/cm.sup.2)                                  ______________________________________                                        1 h    0.4722 ± 0.2483                                                                           0.0608 ± 0.0571                                      3 h           0.1417 ± 0.0522                                                                             0.0140 ± 0.0305                             6 h           0.1417 ± 0.0990                                                                             0.0046 ± 0.0082                             ______________________________________                                    

EXAMPLE 7

The ingredients set forth in the following recipe were weighed and mixedthoroughly to prepare powders.

    ______________________________________                                        Sucralfate, dried powder                                                                              800 mg                                                Malic acid                                            160 mg                  Mannitol                                                 35 mg                Precipitated silicic anhydride                                                                                    5 mg                                      ______________________________________                                    

EXAMPLE 8

The ingredients set forth in the following recipe were weighed, mixedand compressed to prepare troches each weighing 1,600 mg.

    ______________________________________                                        Sucralfate, dried powder                                                                             1,000 mg                                               Malic acid                                           300 mg                   Polyethylene glycol 6000                                                                                             200 mg                                 Sucrose                                                  80 mg                Sodium saccharin                                10 mg                         Flavoring agent                                  10 mg                        ______________________________________                                    

EXAMPLE 9

The ingredients set forth in the following recipe were weighed;hydroxypropyl starch was gelatized with 10 volumes of purified water andmixed with the respective ingredients to prepare suspensions.

    ______________________________________                                        Sucralfate, dried powder 1,000  mg                                            Lactic acid                     mg                     250                    Hydroxypropyl starch            mg            200                             Parahydroxybenzoic acid methyl ester                                                                          3                                                                             mg                                            Parahydroxybenzoic acid propyl ester                                                                          2                                                                             mg                                            Flavoring agent                 mg                  10                        Absolute ethanol                mg                 50                         Purified water to make          ml           10                               ______________________________________                                    

EXAMPLE 10

The ingredients set forth in the following recipes were weighed; using a5% aqueous solution of hydroxypropyl cellulose as a binder, each ofgranulations 1 and 2 was kneaded and forced through a screen to preparegranules; the two batches of granules were mixed to prepare granules.

Granulation 1:

    ______________________________________                                        Sucralfate, dried powder                                                                             1,000 mg                                               Corn starch                                         50 mg                     Hydroxypropyl celulose                   10 mg                                ______________________________________                                    

Granulation 2:

    ______________________________________                                        Tartaric acid          300 mg                                                 Lactose                                                  500 mg               Corn starch                                          100 mg                   Hydroxypropyl cellulose                                                                                                 10 mg                               ______________________________________                                    

EXAMPLE 11

The ingredients set forth in the following recipe were weighed, mixedand compressed to prepare chewable tablets each weighing 2,000 mg.

    ______________________________________                                        Sucralfate, dried powder                                                                             1,000 mg                                               Glucuronic acid                                  300 mg                       Polyethylene glycol 6000                                                                                              100 mg                                Sucrose                                                  590 mg               Aspartame                                               10                    ______________________________________                                                               mg                                                 

EXAMPLE 12

The ingredients set forth in the following recipe were weighed,dispersed in a fused base, agitated and shaped to prepare suppositoriesof 230 mg.

    ______________________________________                                        Sucralfate, dried powder                                                                             1,000 mg                                               Glucuronic acid                                 300 mg                        Polyethylene glycol 1540                                                                                           1,400 mg                                 Polyethylene glycol 6000                                                                                             600 mg                                 ______________________________________                                    

EXAMPLE 13

The ingredients set forth in the following recipe were weighed and mixedwell to prepare an ointment.

    ______________________________________                                        Sucralfate, dried powder                                                                             10 parts                                               Maleic acid                                           4 parts                 hydrophilic ointment JP                                                                                                86 parts                             ______________________________________                                    

INDUSTRIAL APPLICABILITY

The sucralfate preparation of the invention is capable of enhancing theadhesion of sucralfate to the mucosal ulcer site under a nonacidiccondition and can be applied not only to ulcers in the upper digestivetract such as esophagitis and duodenal ulcer but also to ulcers in thelower digestive tract such as proctitis and ulcerative colitis, as wellas to dermal ulcers such as bedsores, stomatitis and the like.

We claim:
 1. A sucralfate preparation comprising group malic acid andsucralfate.
 2. A preparation consisting essentially of an organiccarboxylic acid having at least two malic acid sucralfate, optionally ahydrophilic polymer, and optionally a pharmaceutically acceptablecarrier.
 3. The preparation according to claim 1, wherein the ratio ofthe malic acid to the sucralfate is from 1:1 to 1:20.
 4. The preparationaccording to claim 3, wherein the ratio of the malic acid to thesucralfate is from 1:3 to 1:10.
 5. The preparation according to claim 1which further has a hydrophilic polymer added thereto.
 6. Thepreparation according to claim 5, wherein the hydrophilic polymer is amember selected from the group consisting of alginic acid, sodiumalginate, hydroxypropyl starch, a propylene glycol ester of alginicacid, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium,carboxymethyl starch and a carboxyvinyl polymer.
 7. The preparationaccording to claim 1 which has a dosage form selected from the groupconsisting of a suspension, powder, non-chewable tablet, capsule,granule, suppository, ointment, chewable tablet and troche.
 8. A methodof treating proctitis which comprises administering to a patient in needthereof a therapeutically effective amount of the preparation ofclaim
 1. 9. A method of treating ulcerative colitis which comprisesadministering to a patient in need thereof a therapeutically effectiveamount of the preparation of claim
 1. 10. A method of treatingesophagitis which comprises administering to a patient in need thereof atherapeutically effective amount of the preparation of claim
 1. 11. Amethod of treating esophagitis which comprises administering to apatient in need thereof a therapeutically effective amount of thepreparation of claim
 1. 12. A method for the treatment of dermal ulcerswhich comprises applying to a dermal ulcer of a patient in need of saidtreatment a therapeutically effective amount of the preparationaccording to claim
 1. 13. The method according to claim 12, wherein thepatient's dermal ulcer is a bedsore.
 14. A method for the treatment ofstomatitis comprising administering to a patient in need thereof atherapeutically effective amount of the preparation according toclaim
 1. 15. The sucralfate preparation of claim 2 having saidhydrophilic polymer.
 16. The sucralfate preparation according to claim15, wherein the hydrophilic polymer is a member selected from the groupconsisting of alginic acid, sodium alginate, hydroxypropyl starch, apropylene glycol ester of alginic acid, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose,carboxymethylcellulose sodium, carboxymethyl starch and a carboxyvinylpolymer.
 17. The sucralfate preparation according to claim 2 having adosage form selected from the group consisting of a powder, anon-chewable tablet, a capsule, a granule, a suppository, an ointment, achewable tablet and a troche.